As of 2003 there were 4.4 million AIAN in the U.S., constituting 1.5% of the total U.S. population, with 2.8 million or 1% self-identifying exclusively as AIAN. The U.S. Census Bureau estimates that by 2050 the AIAN population will grow to 3.2 million with a projected rate of increase of 55%, exceeding the projected rate of increase for Whites and comparable to the rate for African Americans. Despite their wealth in cultural and tribal diversity. Natives in the U.S. experience considerable socio-economic disparities. For example, in 2003, AIAN compared to the U.S. population, reported a greater likelihood of living below the poverty level (27% vs. 15%) and lower overall median household incomes ($34,700 vs. $43,500); and reported higher unemployment (15.1% vs. 5.9%). Moreover, 30% of the AIAN population lacks health insurance coverage. Indigenous populations suffer from pervasive patterns of health disparities, unequal burden of chronic illnesses, as well as disproportionate levels of morbidity (e.g., diabetes, cardiovascular disease) and injury-related mortality (e.g., suicide, motor vehicle collisions). Natives also experience high rates of trauma (e.g., injury, motor vehicle accidents, homicide) and violence exposure (e.g., rape, sexual assault, combat exposure) with co-occurring disproportionate rates of psychopathology (i.e., PTSD, depression, anxiety, suicide, AOD disorders). In the U.S., Natives have escalating rates of HIV and other sexually transmitted infections (STI), respiratory and reproductive health problems, as well as premature mortality related to chronic disease states. HIV/AIDS and STI have become major sources of concern for Natives. In a comprehensive review of STI and HIV among AIAN, Kaufmann and colleagues (2007) noted that the epidemiologic evidence points to excessively high case rates of STI among AIAN compared to the general population; with a greater burden borne by Native populations living in closer proximity to one another. For example, in the U.S., AIAN have the second highest rates of Chlamydia and gonorrhea. The potential for exposure to and transmission of HIV is greatly enhanced by these elevated STI rates. Indeed, elevated rates of STI may provide a 2-5 fold increased risk for HIV infection among AIAN in the U.S. According to data from the National HIV/AIDS Surveillance System through December 2008, a cumulative total of 3,741 AIDS cases among AI/AN have been reported to the CDC. In terms of the major modes of transmission, percentages for AIAN men were: MSM (64%), IDU (14%), and MSM/IDU (14%). Note that this last category is higher for AIAN men than any other ethnic group. For AIAN women, the percentages were IDU (37%) and heterosexual contact (50%). Note that the IDU transmission category for Native women is higher than for any other ethnic group. Since 1995, the rate of AIDS diagnosis for AIAN has been consistently higher than the rate for Whites or Asian/Pacific Islanders in the U.S. Additionally, when one takes the relative population size into account, a more disturbing picture emerges. The AIDS case rates for AIAN per 100,000 were 8.5 (11.9 for HIV rates), ranking them just behind Blacks (49.3; 73.7 for HIV rates) and Hispanics/Latinos (15.0; 25.0 for HIV rates). In our research (N=447; HONOR Project, R01MH65871), 30% of Native two-spirit (i.e., AIAN sexual and/or gender minority) men reported that they were HIV+ (19% reported they did not know their status). These numbers are unprecedented and suggest that the HIV/AIDS epidemic for Native MSM may be similar to Black MSM. Natives suffer disproportionate exposure to trauma and mental health disparities. Recent reports demonstrate that Native communities experience higher rates of sexual and physical violence than any other ethnic or racial group in the U.S. Among MSM in our HONOR project, 31% had experienced extreme sexual abuse in childhood. Our previous research with two spirit populations, particulariy MSM, suggest that a history of sexual abuse, substance abuse, poverty, and involvement in sex trade are all related to risky sexual behaviors. Mental health is an important factor in Native HIV risk. Not surprisingly, given the high rates of trauma exposure, it is well documented that Natives have high lifetime rates of both depression and PTSD (15% and 8% respectively; higher than in non-Native groups.^ Mental health issues such as depression, anxiety, PTSD are common mental health outcomes to high rates of trauma exposure and have also been linked to risky sexual behaviors among Natives and two-spirits. Over the past three decades, studies have indicated that there are also high rates of substance use and alcohol misuse among AIAN, although there is tremendous variation over time, by tribe, and by reservation/ Results of the 2005 National Survey on Drug Use and Health indicate that the rate of current illicit drug use was higher among American Indians and Alaska Natives (12.8%) than among persons of other races or ethnicities. The relationship between drug use with precocious sexual activity and potential HIV sexual-risk behavior has been well documented. Moreover, research indicates that substance use may mediate the relationship between traumatic event exposure and sexual risk. Findings in our HONOR study indicated that over 40% of the sample reported lifetime use of narcotics, stimulants, inhalants, and methamphetamine (60% reported lifetime cocaine use). Over 35-40% reported having used stimulants, cocaine, narcotics, methamphetamine, inhalants, and club drugs in the past year. Additionally, over 25% ofthe Native MSM had injected illicit drugs and had traded sex in their lifetime. Native HIV/AIDS risk is both structurally and behaviorally determined and interventions research needs to investigate multiple levels for the highest impact. Concurrent with structural interventions, individual level STI-specific knowledge and skills directly impact choices that influence risk and are also important intervention targets, particulariy for Native MSM and IDUs. At this moment, there is a window of opportunity to intervene with respect to HIV preventive interventions among Native MSM, particularly substance using MSM. This study could provide a body of data upon which to make recommendations for national HIV treatment strategies planning for Native MSM. Our preliminary work among AIAN MSM has been very successful and points to gaps in care and areas for new patient oriented research. Based on our research, reports from individuals we spoke with over the past 7 years and our community forums in the two-spirit communities- the need for HIV preventive intervention development-particularly among substance using twospirit MSM~has become a community imperative. Community members note that rural and reservation-based two-spirit men should also be included in future prevention efforts. The difficulty in accessing or unintentionally outing rural and reservation-based Native MSM requires innovative intervention development and sampling strategies. Moreover, Native MSM who are faced with newly diagnosed HIV are often in psychological crisis. They report depression and anxiety, social isolation, stigma, demoralization, anger, and, in the extreme, suicidal ideation. Their emotional distress is compounded by fears about transmitting the virus to family members and partners. Despite their urgent need for psychological and substance abuse intervention, most newly diagnosed two-spirit men do not receive any culturally tailored mental health or substance abuse treatment, even rudimentary counseling. Urban Native health clinics as well as tribal health clinics lack the mental health and HIV prevention infrastructure to address these needs in the general Native population already, and few professionals are available to provide education to providers or care to two-spirit patients. We propose to develop an online HIV preventive intervention for two-spirit MSM. The project has the potential to fill an enormous gap in HIV prevention needs among two-spirit men and, because of its online delivery format, could be widely disseminated throughout the country. Two-spirit men in rural areas, particularly isolated, would be ideally suited to benefit from such a program. Our plans are to incorporate a social networking peer component in the online intervention to provide a culturally grounded two-spirit intervention that facilitates positive sexual health behaviors, decreases substance use and HIV risk behaviors, and provides the peer support that may best address their needs.